Mitigation of hematopoietic acute radiation syndrome (ARS) by inhibition of tyrosine kinase FGR - ionizing radiation (IR) causes acute damage to both hematopoietic (H) and gastrointestinal (GI) systems

The National Institutes of Health Office of the Director awarded a $1,085,184 Cooperative Agreement to the University of Pittsburgh on September 19, 2025, to support research on mitigation of hematopoietic acute radiation syndrome through inhibition of the tyrosine kinase FGR, under the Trans-NIH Research Support program (CFDA 93.310).

The research addresses the lack of FDA-approved therapies for hematopoietic acute radiation syndrome that can be administered more than 24 hours after total body irradiation. The award funds development of novel medical countermeasures targeting FGR, a non-receptor tyrosine kinase identified as a master regulator of inflammation in bone marrow following radiation injury. Preliminary data demonstrates that FGR knockout mice and mice treated with the FGR inhibitor TL02-59 at 24 hours post-irradiation achieved complete survival, with evidence of increased radioresistance in bone marrow cells and reduced inflammatory protein upregulation. The research also identified CD91 as a receptor upstream of FGR whose genetic ablation phenocopies FGR inhibition.

Work is performed in Pittsburgh, Pennsylvania, with a period of performance extending through August 31, 2030. The assistance type is a Cooperative Agreement, which typically involves substantial federal involvement in the execution of the project beyond funding and administrative oversight.

The hematopoietic system damage is known as the acute hematopoietic radiation syndrome (H-ARS). There are few FDA approved therapies to treat H-ARS that can be given after 24H. Therefore, there is an urgent need for novel medical countermeasures (MCMS) targeting master regulators of inflammation, proliferation, and tissue regeneration in response to TBI injury. We have discovered a novel target of H-ARS FGR, a non-receptor tyrosine kinase that is a master regulator gene that promotes inflammation in the bone marrow after TBI. In our preliminary data we show: 1) significant increase in survival of FGR knockout (FGR-/-) mice after total body irradiation (TBI); 2) complete survival of mice that received FGR-inhibitor, TL02-59 treatment 24H after TBI; 3) induction of proteins that protect ARS including G-CSF and GM-CSF following TBI in FGR-/- mice bone marrow relative to control mice, 4) the FGR-/- bone marrow is more radioresistant evidenced by the survival assay of CFU-gemm colonies; 5) reduced post-TBI upregulation of inflammatory proteins in the bone marrow of FGR-/- mice, 6) FGR inhibitor TL02-59 reduced the secretion of inflammatory proteins from irradiated cells, 7) identification of CD91 as receptor upstream of FGR, and 8) genetic ablation of CD91 phenocopies FGR inhibition by TL02-59. We hypothesize that FGR is a master regulator of inflammation. TBI causes massive cellular necrosis and release of endogenous ligands of CD91 and induction of FGR. Engagement of CD91 by its ligands leads to significant activation of FGR in the bone marrow cells which induces the release of a battery of inflammatory cytokines, immediate systemic inflammation, and further cell death. We further hypothesize, that FGR inhibition by TL02-59 or antagonizing CD91, would lead to suppression of inflammation, recovery of bone marrow, and improvement in survival. We will use a 1) our novel inducible FGR knockout (CFGR-/-) mouse model, conditional CD91 knockout (CD91-/-) mice, hematopoietic specific FGR knockout (H-FGR-/-) mice, and a small molecule inhibitor of FGR TL02-59 as a new approach towards developing a novel MCM after TBI. We will test the hypothesis that following irradiation, induction of FGR mediates inflammation and cell death, and inactivation or inhibition of FGR after 24H, directly or indirectly, will significantly increase survival by mitigating H- ARS. We will investigate upstream and downstream targets of FGR and delineate underlying mechanism of hematopoietic protection by FGR inhibition. In aim 1, we will first establish that genetic ablation or pharmacologic inhibition of FGR mitigates H-ARS. In aim 2, we will establish the mechanism of ARS mitigation by TL02-59 is from H-ARS mitigation, and in aim 3, we will establish the link between FGR and inflammation in TBI mice. Successful completion of the proposed aims would lead to the discovery of a most potent mitigator of H-ARS yet reported. The FGR inhibitor, TL02-59 mitigates H-ARS in 100% of treated mice at 24 H after TBI. A drug that inhibits the function of one protein indicates that IT is a master regulator of the H-ARS.